Field of the Invention
This invention is directed to the control of the morphologies within polymer matrices in facilitating the design of release rate profiles of agents from within these matrices.
Description of the State of the Art
Biomaterials research is continuously striving to improve the compositions from which medical articles, such as medical devices and coatings for medical devices, are produced. An example of a medical article is an implantable medical device.
A stent is an example of an implantable medical device that can benefit from improvements, such as a coating that can be used as a vehicle for delivering pharmaceutically active agents in a predictable manner. Stents can act as a mechanical intervention to physically hold open and, if desired, expand a passageway within a subject. Typically, a stent may be compressed, inserted into a small vessel through a catheter, and then expanded to a larger diameter once placed in a proper location. Examples of patents disclosing stents include U.S. Pat. Nos. 4,733,665, 4,800,882 and 4,886,062.
Stents play an important role in a variety of medical procedures such as, for example, percutaneous transluminal coronary angioplasty (PTCA), which is a procedure used to treat heart disease. In PTCA, a balloon catheter is inserted through a brachial or femoral artery, positioned across a coronary artery occlusion, inflated to compress atherosclerotic plaque and open the lumen of the coronary artery, deflated and withdrawn. Problems with PTCA include formation of intimal flaps or torn arterial linings, both of which can create another occlusion in the lumen of the coronary artery. Moreover, thrombosis and restenosis may occur several months after the procedure and create a need for additional angioplasty or a surgical by-pass operation. Stents are generally implanted to reduce occlusions, inhibit thrombosis and restenosis, and maintain patency within vascular lumens, such as the lumen of a coronary artery.
Stents are also being developed to provide a local delivery of agents. Local delivery of agents is often preferred over systemic delivery of agents, particularly where high systemic doses are necessary to achieve an effect at a particular site within a subject—high systemic doses of agents can often create adverse effects within the subject. One proposed method of local delivery includes coating the surface of a medical article with a polymeric carrier and attaching an agent to, or blending it with, the polymeric carrier.
Agent-coated stents have demonstrated dramatic reductions in the rates of stent restenosis by inhibiting tissue growth associated with the restenosis. Restenosis is a very complicated process and, agents have been applied, alone and in combination, in an attempt to circumvent the process. The process of restenosis in coronary artery disease is derived from a complex interplay of several implant-centered biological parameters. These are thought to be the combination of elastic recoil, vascular remodeling, and neointimal hyperplasia. Since restenosis is a multifactorial phenomenon, the local delivery of agents from a stent can be improved through the design of a release rate profile that would deliver agents as needed from the stent in a controlled and predictable manner. For example, one method of applying multiple agents involves blending the agents together in one formulation and applying the blend to the surface of a stent in a polymer matrix. A disadvantage of this method is that the agents are released from the matrix through a somewhat variable polymeric matrix morphology and, as such, compete with one another for release in an unpredictable manner. Other methods suffer from a sudden initial release of agents in high amounts, known as a burst release, which can prevent a prolonged release of agents in sufficient concentrations.
In some cases, polymeric matrices that are otherwise desirable are unable to meet particular performance characteristics that are required by some medical articles. Often, the inability to meet particular performance characteristics results from combining components that are desirable independently but form undesirable morphologies that cannot meet the required performance characteristics when formed into a polymeric matrix.
In other cases, polymeric matrices that are desirable upon manufacture can be unpredictable in performance at the time of use. Morphological changes are known to happen to medical articles during processing and storage, as well as after application in vivo. Unfortunately, the predictability of a medical article can rely on the ability to control these changes.
Those skilled in the art will appreciate a reliable way of controlling the performance of medical articles which includes controlling the release of agents, since a controlled release of agents can be critical to preventing, inhibiting, treating or mitigating a disease process. The ability to select and design the morphology of a polymeric matrix can not only provide for control over the release rate of agents but can also can assist in designing and maintaining the physical and mechanical properties of medical devices and coatings. Accordingly, control over the morphology of a polymeric matrix is an important design consideration and one of the next hallmarks in the development of novel medical articles.